Coronary heart disease (CHD) is a leading cause of troublesome quality of human life and mortality among the populations of the developed nations as well as the economically fast-growing countries, accompanied by worldwide rise in obesity, diabetes, including among young adults, due to high-calorie diets and poor exercise time. The cardiovascular disease is characterized by clogged arteries and reduced supply of blood and nutrients to the heart muscle caused by lipid deposition inside the arterial wall. Hyperlipidemia or hyperlipoproteinemia (form of lipid-protein complexes) may be caused by genetic factors or by obesity and metabolic disorders. Lipid-protein complexes are spherical aggregates consisting of a hydrophobic core composed of lipids (triglycerides and cholesterol esters) surrounded by a hydrophilic exterior shell of about 2 nm composed of apoproteins, cholesterol, and phospholipids. The hydrophilic polar surface keeps the lipids dissolved and circulating in the plasma. Based on size and density, four main lipoproteins are prevalent in the plasma:chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL or LDL-C), and high density lipoprotein (HDL or HDL-C). Chylomicrons and VLDL are rich in triglycerides and cholesterol. They are the sources of fatty acids in muscle and adipose tissues. LDL-C particles are rich in cholesterol and are produced in the liver from dietary cholesterol, from liver-synthesized cholesterol, and from remnants of chylomicrons and VLDL that have entered the extrahepatic tissues from the general circulation [see Ziegler, A. et al., Color Atlas of Pharmacology, 2nd Edition, pp. 154-157, Thieme Publishers, 2000].
High levels of LDL-C (referred to as ‘bad cholesterol’) is a well-established major risk factor in CHD, but can be effectively treated with HMG-CoA reductase inhibitors (statins) leading to substantial reduction in cardiovascular morbidity and mortality [see Scandinavian Simvastatin Study Group, Lancet 344, 1383-1389 (1994)]. HDL-C particles (referred to as ‘good cholesterol’) are responsible for a cleansing mechanism called ‘reverse cholesterol transport’, where the cholesterol is transported from extrahepatic tissues to the liver for catabolic destruction and excretion. It is widely accepted that low levels of HDL-C and high levels of triglycerides in plasma are important risk factors contributing to CHD [see NCEP Panel, Circulation 89, 1329 (1994)].
Levocarnitine (L-carnitine or vitamin BT) belongs to a class of water soluble vitamins which include vitamin B12, folic acid, biotin, vitamin B6, and mevalonic acid. It occurs naturally, and serves as a cofactor in fatty acid metabolism for energy production. This cofactor functions by binding activated fatty acids in the form of acyl carnitine (carnitine shuttle). Use of l-carnitine in the treatment of hyperlipoproteinemia, hyperlipidemia, and myocardial dysfunction has been the subject of intense investigation [see, for example, Carazza, C., U.S. Pat. No. 4,255,449; Ramacci, M., U.S. Pat. No. 4,315,944; Siliprandi, N., Hypolipidemic Drugs, G. Ricci (Ed.), New York: raven, 1982; Yamazaki, N., Lipid 1(2) (1990); Pauly D. F. et al., Am. J. Kidney Dis. 41, S35-S43 (2003); Calvani, M., et al., Basic Res. Cardiol. 95, 75-83 (2000)]. L-carnitine has also been reported to be useful as an adjuvant therapy in the management of renal anemia [Cianciaruso, B., et al., Contrib. Nephrol. 137, 426-430 (2002)]. Propionyl carnitine (the propionic ester of carnitine) has been shown to improve cardiac function [see, for example, Wiseman, L. R, et al., Drugs Aging 12, 243-248 (1998); Ferrari, R. et al., Developments in Cardiovascular Medicine 162, 323 (1995)]. Acetyl carnitine has been proposed as a possible therapeutic agent for Alzheimer's disease [Pettegrew, J. W., et al., Expert Review of Neurotherapeutics 2, 647-654 (2002)]. Recently, CPS 124, a carnitine monothiophosphate derivative which is a reversible and competitive inhibitor of carnitine palmitoyl transferase I, is reportedly undergoing clinical development for the treatment of non-insulin dependent diabetes mellitus (NIDDM) [Anderson, R. C., Curr. Pharm. Des. 4, 1-16 (1998)]. Nicotinyl carnitine derivatives have been studied as anticholesteremics and hypolipemics [Chibata, I., et al., U.S. Pat. No. 4,032,641].
In humans, fibrates such as clofibrate, bezafibrate, fenofibrate, etofibrate, gemfibrozil, and G10-2331, which are agonists of PPAR-alpha, have been successfully used to treat hypertriglyceridemia. They function by increasing the clearance and decreasing the synthesis of VLDL. The fibrates, however, have only a modest effect (10-20%) in increasing HDL-C levels [see, for example, Staels, B., et al., Circulation 98, 2088-2093 (1998); Harwood, H. J., et al., Emerging Drugs 3, 147 (1998)]. Clinical development of cardioprotective HDL-C elevating agents is a major therapeutic goal. Recently, it was shown that oxa-substituted α,ω-alkanedicarboxylic acids and related compounds raise serum HDL-levels significantly [see, for example, Bisagaier, C. L., et al., U.S. Pat. No. 5,756,544; Dasseux, J. L., et al., U.S. Pat. No. 6,646,170]. In particular, CI-1027 has been in clinical trials. Also, long chain α,ω-alkanedicarboxylic acids are also in clinical development as hypolipidemic agents [see Bar-Tana, J. U.S. Pat. Nos. 4,689,344 and 4,711,896].
The peroxisome proliferator activated receptor (PPARα) is one among a set of ligand-activated transcription factors in the nuclear receptor superfamily. Other distinct PPAR subtypes are PPARγ, PPARδ, and PPARβ [see Mangelsdorf, D. J., et al., Cell 83, 841-850 (1995); Green, S., et al., Mol. Cell. Endocrinol. 100, 149-153 (1994); Dreyer, C., et al., Cell 68, 879-887 (1992); Kliewer, S. A., et al., Recent Prog. Horm. Res. 56, 239-263 (2001); Berger, J., et al., Annu. Rev. Med. 53, 409-435 (2002)]. In particular, PPARγ has been shown to be the primary receptor involved in the antidiabetic activity of thiazolidinediones (TZDs) [see Tong, Q., et al., Rev. Endocr. Metab. Disord. 2, 349-355 (2001); Rosen, E. D., et al., Genes Dev. 14, 1293-1307 (2000)]. Current discovery efforts in metabolic diseases are focused on the design of balanced, dual (PPAR)α/γ agonists to treat hyperlipidemia, type 2 diabetes (NIDDM) and obesity. Interestingly, many of the lead dual (PPAR)α/γ agonists entering preclinical and clinical development contain the essential structural features of classical fibrates designed to block the β-oxidation pathway of fatty acids [see Xu, Y., et al., J. Med. Chem. 47, 2422-2425 (2004); Koyama, H., et al., J. Med. Chem. 47, 3255-3263 (2004)].
In view of the extensive work in the treatment of hyperlipoproteinemia, hyperlipidemia, and myocardial dysfunction with L-carnitine, L-propionyl carnitine, CI-1027 and its analogs, and fibric acids, it is surprising that covalent conjugates of any two or more of these drugs have not been proposed. Therefore, the present invention introduces a novel concept referred to as ‘double prodrug’ approach which involves the preparation of novel covalent conjugates comprising two or more drugs, and their use in the treatment of various cardiovascular disorders. A suitable covalent attachment of two more of these cardiovascular agents will have a significant therapeutic value in that a single molecular entity may have multiple therapeutic effects resulting from diverse, but synergistic mechanism of action, and controlled release of both drugs in vivo through enzymatic hydrolysis of the conjugate. The concept of the present invention is not limited to cardiovascular applications; other therapeutic applications, including CNS disorders, diabetes, cancer, inflammation, and the like are also contemplated